Health outcomes associated with micronutrient-fortified complementary foods in infants and young children aged 6–23 months: a systematic review and meta-analysis

Summary Background Appropriate feeding of infants and young children is essential for healthy growth and the prevention of stunting, wasting, and overweight. We aimed to assess the beneficial versus harmful effects of providing fortified complementary foods to children in the complementary feeding period. Methods In this systematic review and meta-analysis, we searched the databases Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, Global Index Medicus, Web of Science, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform from inception to March 9, 2021. We included randomised controlled trials and controlled clinical trials done in infants and children aged 6–23 months with no identified health problems. Consumption of foods fortified centrally (ie, during industrial processing) with one micronutrient or a combination of vitamins, minerals, or both was compared with the same complementary foods, but without micronutrient fortification. Two review authors independently screened studies for eligibility, extracted data, assessed risk of bias, and rated the certainty of the evidence. The main outcomes were growth (measured by Z scores for weight for age, weight for height or length, and height or length for age, or other growth measures), stunting, wasting, nutrient adequacy or excess, anaemia, haemoglobin concentration, iron status, serum zinc concentration, and serum retinol concentration. We used a random-effects meta-analysis for combining data. This study is registered with PROSPERO, CRD42021245876. Findings We included 16 studies with 6423 participants, 13 of which were done in malaria-endemic areas. Overall, 12 studies were included in the quantitative syntheses. We identified five further ongoing studies. There was no difference between participants who received fortified complementary foods and those who received non-fortified complementary foods in weight-for-age Z scores (mean difference −0·01, 95% CI −0·07 to 0·06; five trials; 1206 participants; moderate-certainty evidence), weight-for-height or length Z scores (−0·05, −0·19 to 0·10; four trials; 1109 participants; moderate-certainty evidence), and height or length-for-age Z scores (−0·01, −0·21 to 0·20; four trials; 811 participants; low-certainty evidence); stunting and wasting were not assessed in any study as outcomes. Moderate-certainty evidence from six trials with 1209 patients showed that providing fortified complementary foods to children aged 6–23 months reduced the risk of anaemia (risk ratio 0·57, 95% CI 0·39 to 0·82). Those who received fortified complementary foods compared with those who did not had higher haemoglobin concentrations (mean difference 3·44 g/L, 95% CI 1·33 to 5·55; 11 trials; 2175 participants; moderate-certainty evidence) and ferritin concentration (0·43 μg/L on log scale, 0·14 to 0·72; six trials; 903 participants; low-certainty evidence). The intervention led to no effects on serum zinc concentration (−0·13 g/dL, −0·82 to 0·56; two trials; 333 participants; low-certainty evidence) and serum retinol concentration (0·03 μmol/L, −0·02 to 0·08; five trials; 475 participants; moderate-certainty evidence). Interpretation Fortified complementary foods are effective strategies to prevent anaemia in infants and young children aged 6–23 months in malaria-endemic regions. Effects of complementary food fortification should be further investigated in low-income and middle-income countries, but should also be assessed in high-income countries, and in regions where malaria is not endemic. Funding WHO.


Introduction
Complementary feeding is the transition from exclu sive breastfeeding to family foods, typically from 6 months to 23 months of age. 1 This period is crucial for physical, cognitive, and motor development, and during this time infants and young children need a great dietary diversity to ensure their nutrient needs are met. 2 The low mineral content of breast milk, the relatively small amount of complementary foods consumed, their potentially inadequate nutrient density, low consumption of haem ironcontaining meat, and the relatively high requirement of micronutrients can lead to nutrient deficiencies during this period of growth. 3 Micronutrient deficiencies are common in lowincome and middleincome countries, affecting more than 2 billion people worldwide. 4,5 The highest nutrient gaps in the comple mentary feeding period have been described for iron, vitamin A, vitamin B12, zinc, and calcium. 4,5 Several strategies have been proposed to provide target nutrients to infants and young children. These strategies include, besides diversified diets, fortified complementary foods, fortified animal milk, 6 micro nutrient powders, 7 and small quantities of lipidbased nutrient supplements. 8 Food fortification is defined as the addition of micro nutrients to processed foods with the aim to increase the intake of these micronutrients and thereby correct or prevent micronutrient deficiencies. 9 Complementary foods can be fortified either centrally (ie, during industrial processing) or at the point of use (home fortification). 9 In malariaendemic regions, the safety of iron preparations administered through home fortification has raised many questions, 10 as the malaria parasite requires iron for growth 11 and randomised controlled trials have indicated that a bolus of iron taken in a single dose might lead to adverse effects, such as increased risk of hospital admission, primarily due to malaria and infectious disease, and mortality, in these regions. 12,13 As fortified processed complementary foods enable iron to be consumed in smaller amounts throughout the day, and therefore absorbed more slowly, this form of iron administration might be a preferred alternative in these regions. 10 Health effects of pointofuse fortification of comple mentary foods in children aged 6-23 months were assessed in a recent systematic review. 7 Several trials exist on the potential beneficial and harmful effects of complementary feeding with centrally fortified foods, [14][15][16][17][18][19][20][21] although there is currently no uptodate systematic review summarising potential health effects of adding micronutrients to industrially processed and widely consumed complementary food products. 22 We aimed to assess the effects of micronutrientfortified complementary food compared with the unfortified version of the same complementary food on beneficial or harmful dietary and health outcomes in infants and young children aged 6-23 months.

Search strategy and selection criteria
For this systematic review and metaanalysis, an infor mation specialist experienced in systematic reviews

Research in context
Evidence before this study Fortified complementary foods are processed foods enriched with essential micronutrients, with the aim of preventing or correcting deficiency of one or more micronutrients in the critical period of complementary feeding. They provide an alternative to home or point-of-use fortification with micronutrient powders or crushable or soluble micronutrient tablets, which were shown in recent systematic reviews to be effective tools to reduce anaemia in children in the complementary feeding period in low-income and middleincome countries. We did a preliminary search of PubMed, Embase, and the Cochrane Library for existing systematic reviews and meta-analyses evaluating the health impact of fortified complementary foods in infants and young children aged 6-23 months using the search terms "fortified" OR "fortification" AND "complementary" published up to Jan 15, 2021. No language restriction was applied. The preliminary investigation revealed systematic reviews assessing the effects of other existing nutritional strategies, including interventions with small-quantity lipid-based nutrient supplements, fortified milk, and home fortification with micronutrient powders. Some systematic reviews included a wide range of interventions, including industrially fortified foods. However, these reviews were narrow in terms of investigated outcomes and described studies from 2006 to 2014. The present systematic review and meta-analysis was done to address the existing gap and to inform the process of updating WHO guidance on feeding of infants and young children aged 6-23 months.

Added value of this study
To our knowledge, this is the first systematic review summarising evidence on the consumption of fortified complementary foods compared with the unfortified version of the same complementary foods in infants and young children aged 6-23 months. We showed that fortified complementary foods probably reduce anaemia in infants and young children in malaria-endemic regions. We showed that fortification with the applied micronutrient composition and doses probably makes little or no difference to growth outcomes. However, the diversity of foods fortified and the micronutrients used for fortification, and the differences in micronutrient doses used for fortification and in baseline characteristics of children, including their anaemia and malaria status, limit our ability to understand how, when, and where this intervention is the most effective and safe.

Implications of all the available evidence
Our study suggests that interventions with fortified complementary foods are effective strategies to prevent anaemia in infants and young children aged 6 months to 2 years in malaria-endemic regions. Our findings support the need for further studies investigating health-related outcomes associated with fortified complementary foods in regions where malaria is not endemic and in high-income countries. More evidence is needed to better understand what level of fortification can lead to adequate or excess nutrient intake and related safety issues. It should be further investigated whether these products lead to the displacement of other foods and how they affect vitamin and mineral status, stunting, and wasting.
(MIM) searched the following electronic databases and trial registers from the inception of each database up to March 9, 2021 [2][3][4]. We tried to identify other potentially eligible trials or ancillary publications by searching the reference lists of included trials and related systematic reviews, metaanalyses, and health technology assessment reports. Study authors were not contacted, and articles were translated into English if necessary.
We included randomised controlled trials with both individual and cluster randomisation and controlled clinical trials, if concurrently controlled. Included children were aged 6-23 months at the start of the intervention. We intended to include apparently healthy children from the general population, although some might have been at risk of having highly prevalent diseases (eg, malaria, HIV, diarrhoea, and under nutrition). The eligible intervention was consumption of fortified complementary products (excluding milk and milkbased formula), fortified centrally with one micro nutrient or a combination of vitamins, minerals, or both. We excluded food supplements, micronutrient powders, or any other ways of home (pointofuse) fortification. The comparator was consumption of an unfortified version of the same complementary product.
Pairs of review authors (IC, RF, ÉS, and SL) independently screened titles and abstracts of every retrieved record using Covidence. Full texts of all potentially relevant records were screened for eligibility. Any disagreements were resolved through consensus or by recourse to a third author (IC or SL). All records excluded after fulltext assessment are listed in the appendix (pp . From fulltext publications, we extracted data on study methods, participants, interventions, controls, outcomes, sources of funding, and potential conflict of interest statements. Data were extracted by one reviewer (IC or RF) and checked for completeness, accuracy, and consistency by a second reviewer (IC or RF).
We included abstracts and conference proceedings, but did not use them for data extraction, because they do not fulfil the CONSORT requirements. 23 Data available as study results in trials registries were also extracted.
Two review authors (ÉS and SL) independently assessed the risk of bias of each included trial. Any disagreements were resolved by consensus. Risk of bias was evaluated with version 2 of the Cochrane risk of bias tool for randomised trials (RoB 2). 24 Overall risk of bias was defined for each trial as the least favourable assessment across the domains of bias.

Outcomes
The outcomes of interest reflect the actual public health need on information and were defined by the WHO guideline development group (GDG) on comple mentary feeding of infants and young children aged 6-23 months. The main outcomes were growth (measured by Z scores for weight for age, weight for height or length, and height or length for age, or other growth measures), stunting, wasting, nutrient adequacy or excess, anaemia, haemo globin concentration, iron status, serum zinc con cen tration, and serum retinol concentration. Additional outcomes were allcause mor tality, adverse effects, mental and motor skill develop ment, morbidity, ferritin concentration, serum or urine con cen tration of other vitamins or minerals, gut microbiota composition, taste preference, and displace ment of other foods. We included outcomes as measured at any given timepoint.

Data analysis
We a priori planned to undertake a metaanalysis for all outcomes for which we judged the partici pants, inter ventions, comparisons, and outcomes to be sufficiently similar to ensure a result that was clinically meaningful.
For dichotomous data, we present results as risk ratios or odds ratios (ORs) with 95% CIs. For continuous data, we use mean differences with 95% CIs for studies measuring outcomes in the same way, and standardised mean differences with 95% CIs for studies measuring outcomes in various ways.
We combined results from clusterrandomised and individually randomised studies. Where trial authors had adjusted their results for the effect of clustering, we aimed to extract the clusteradjusted risk ratios and SE and enter the natural log of these into Review Manager (RevMan) using the generic inverse variance method, as recommended by Higgins and colleagues. 25 Otherwise, we extracted the simple summary data for all relevant outcomes and calculated crude risk ratios and 95% CIs using RevMan. We adjusted for the effects of clustering using the approximate analysis method. 25 This involves inflating the SE of the risk ratio using an estimate of the design effect and entering the natural logs of the adjusted risk ratios and corresponding SEs into RevMan using the generic inverse variance method. The intra cluster correlation coefficient was not reported in any of the trials, so the value of 0·03 was used, as suggested by Leyrat and col leagues. 26 A sensi tivity analysis with respect to the intra cluster correlation coefficient was For Covidence see https://www. covidence.org/ not undertaken. We examined the potential effects of clustering using sensitivity analyses.
For outcomes with skewed data (presented as geometric means or medians), we calculated log transformed data for all studies and did a metaanalysis on the scale of the logtransformed data. For multiarm studies, we included the directly relevant arm only. 27 If a study compared two possible fortified products with one nonfortified com parator, we combined groups to create a single pairwise comparison. 28 We assessed methodological heterogeneity by examining risk of bias, and clinical heterogeneity by examining similarities and differences between studies regarding types of participants, interventions, and outcomes. We considered the size and direction of effect and used a standard χ² test with a significance level of α=0·1 19 and the I² statistic, which quantifies inconsistency across trials, to assess the effect of heterogeneity on the metaanalysis. 29,30 We explored heterogeneity through prespecified subgroup analyses.
We used funnel plots to assess reporting bias and to investigate the relationship between effect size and SE when at least ten studies were included in a metaanalysis. The degree of funnel plot asymmetry was quantified using Egger's test. 31 The Robvis tool was used to visualise risk of bias.
As we expected differences between studies in both the population and the intervention, we decided to combine the data using a randomeffects model. We used Mantel Haenszel weighting for dichotomous outcomes and inverse variance for continuous outcomes or in case both individually and clusterrandomised trials were included in a metaanalysis.
We planned to do subgroup analyses for the following characteristics: age groups, different types of nutrients added through fortification, different types of products fortified, duration of intervention, the country income classification (defined according to the World Bank country income classification 32 ), anaemia status at the start of the intervention, and sponsor. The potential effects of clustering were examined by sensitivity analyses.
We did statistical analyses using RevMan 5 (version 5.4.1). We followed the GRADE approach to rate the certainty of evidence. 33 The methodology and the results are reported according to the Preferred Reporting Items for Systematic reviews and Meta Analyses (PRISMA) reporting guideline. 34 This study is registered with PROSPERO, CRD42021245876.

Role of the funding source
The present work serves as a background evidence review for the WHO guidelines on feeding of infants and young children aged 6−23 months. The questions guiding the review were discussed and developed, and the study protocol was approved, by the WHO GDG on complementary feeding of infants and young children aged 6-23 months. WHO and its GDG had no role in data collection, analysis, or interpretation. The WHO GDG members peer reviewed the systematic review report. The present manuscript is based on the report. WHO and its GDG did not participate in the writing of the present manuscript.

Results
We retrieved 15 486 unique records through database searching and six through citation searching (figure 1). After removing duplicates, 8322 records were screened on the basis of their titles and abstracts (figure 1). We evaluated 503 full texts or records to determine their eligibility for inclusion in the review. 21 studies met our inclusion criteria (16 studies with fulltext publications   (2016), 39 Krebs et al (2013), 40 Sheng et al (2019)  Vitamin A1 is also known as retinol. Vitamin B1 is also known as thiamine. Vitamin B2 is also known as riboflavin. Vitamin B3 is also known as niacin. Vitamin B6 is also known as pyridoxine. Vitamin B12 is also known as cyanocobalamin. Vitamin C is also known as ascorbic acid. Vitamin D3 is also known as cholecalciferol. CCT=controlled clinical trial. RCT=randomised controlled trial. *Further details on the amount of micronutrients used for fortification can be found in the appendix (pp 59-60).  [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56]. Eight studies were random ised controlled trials randomised at the indi vidual level, 14,35,37,44,[46][47][48]50 one was a controlled clinical trial, 38 and seven were clusterrandomised controlled trials. 2,19,36,39,42,43,45 Most of the studies were done in upper or lowermiddle income countries. One study was done in a highincome country, 50 and no study was done in a lowincome country. Three studies were done in nonmalariaendemic areas (appendix pp 57-58). 52 Participant age ranged from six to 60 months (three studies included children aged up to 60 months). When possible, we only included data for children younger than 24 months. Sample sizes ranged from 40 50 to 2250. 2 Three studies had an intervention duration of three subsequent feeding sessions 50 to 3 consecutive days. 37,38 Among studies investigating longerterm effects of fortified complementary food consumption, the inter vention duration lasted between 10 weeks 48 and 4 years. 2,51 Fortified products were cereals in most of the cases (appendix pp 59-62).
Iron status was measured as ferritin concentration, body iron, or free erythrocyte porphyrin. A daily dose of iron added to the complementary food products via fortification varied among studies, with a daily amount of 0·36 mg, 39 2·5 mg, 36 3·66 mg, 47 4·6 mg, 48 or 4·93 mg 19 of elemental iron consumed, or with more than 10·9 mg per day or less than 21·9 mg per day. 49 Children receiving ironfortified complementary foods for 12 weeks to 12 months had, on average, higher ferritin concentrations at followup than children consuming nonfortified complementary food (mean difference 0·43 μg/L on log scale, 95% CI 0·14−0·72; six trials; 903 participants; lowcertainty evidence; figure 5). One study 39 described rice cereal fortified with iron, zinc, and vitamin B12 to be effective in increasing body iron, whereas another study 19 found no effects of rusks fortified with iron, zinc, and calcium on free erythrocyte porphyrin (appendix pp 89−90).
Serum zinc concentration was measured in two studies, in which less than 10·26 mg per day 49 and 6 mg per day 47 daily doses of zinc were provided, in combination with other micronutrients. The percentage of children with low serum zinc concentrations (cutoff values defined as serum zinc <10·7 μmol/L 49 or <9·9 μmol/L 47 ) at baseline was 3·6% (among 120 participants) 49 and 43-48% (among 289 partici pants). 47 Children consumed fortified food for 6 months
In three studies assessing vitamin A deficiency after an intervention period from 3 months to 12 months, 35,46,49 there were no differences in the likelihood of having vitamin A deficiency (defined as serum retinol concen trations of <0·70 μmol/L) at followup between children consuming fortified and unfortified comple mentary foods (risk ratio 0·97, 95% CI 0·24−3·90; three trials; 257 partici pants; verylowcertainty evidence; appendix p 91). One study reported on nutrient adequacy and described that children in the fortified cereallegume blend group consumed two to three times the recommended intake from zinc and vitamin A as a result of fortification. 14 Mental skill development was assessed in two studies (508 participants), one 44 measuring it on the first version of the Bayley Scales of Infant Development (BSID I), and the other 39 on BSID III. Overall, children consuming fortified complementary foods had higher scores than children consuming the unfortified version of the same complementary food (mean difference 0·80, 95% CI 0·12−1·48; moderatecertainty evidence; appendix p 90). Motor skill development was reported as fine motor and gross motor score (measured on BSID III) in one study, 39 as psychomotor score (measure on BSID I) in one study, 44 and 25item motor development score (BSID II) in one study. 47 Psychomotor development was im proved in children consuming fortified complementary food (mean difference 1·13, 95% CI 0·35−1·91; two trials; 661 participants; lowcertainty evidence; appendix p 91). This effect was not seen in the study investigating fine and gross motor scales separately (appendix p 91). 39 One trial with 97 children reported on morbidity, 49 defined as number of new episodes per 100 days at risk. The number of cases of diarrhoea, acute respiratory tract infection, and fever disease episodes did not differ between children consuming fortified and nonfortified complementary foods (verylowcertainty evidence; appendix p 90).
Acceptability of fortified compared with nonfortified complementary foods was measured in two randomised controlled trials 37,50 and one controlled clinical trial 38 with a total of 215 children. All studies evaluated acceptance on a 9point hedonic scale (answers of toddlers interpreted by mothers), with a higher score representing better acceptance. Degree of liking did not differ significantly in any of these studies between fortified and nonfortified groups.
No studies reported data on the following prespecified outcomes: stunting and wasting, nutrient intakes above the upper limit, allcause mortality, gut microbiota composition, or displacement of other foods.
Adverse effects were reported in one study, in which fortified complementary foods "were well tolerated and no side effects were reported in either group". 36 For the growth outcome, no relevant subgroup effects were detected, and clusterrandomised controlled trials were shown to have no effect on the direction of the pooled estimate in sensitivity analyses. For the outcomes of anaemia prevalence, haemoglobin concentration, and iron status, inconsistent differences were seen among age subgroups and the types of products that were fortified. Baseline anaemia status did not affect favourable effects of fortified complementary foods on post intervention anaemia prevalence and iron status, but had effects on haemoglobin concentrations (all subgroup analyses are shown in the appendix pp 73-91). The beneficial effect of fortified complementary foods on haemoglobin concentration was no longer significant when all of the clusterrandomised controlled trials were excluded in the sensitivity analysis (mean difference 4·48 g/L, 95% CI -0·10 to 9·05; five trials; 44,46−49 903 partici pants), but were still significant in the case of iron status (0·64 μg/L on log scale, 95% CI 0·23 to 1·05; three trials; 47−49 423 participants).

Discussion
To our knowledge, this is the first systematic review summarising evidence on the consumption of fortified complementary foods compared with the unfortified version of the same complementary foods in infants and children aged 6-23 months. Results showed that providing fortified complementary foods to children probably reduces anaemia by 43%. Participants who receive fortified complementary foods probably have higher haemoglobin and might have higher ferritin concentrations than those who receive nonfortified complementary foods. Fortification with the applied micronutrient composition and doses probably makes little or no difference to growth outcomes. The inter vention might result in little to no effect on zinc and vitamin A concentrations; there is no available evidence of effects on other vitamin and mineral concentrations. Acceptability of fortified and nonfortified comple mentary products in terms of sensory characteristics might not differ. Results of this systematic review are limited to preventive purposes; effectiveness of food fortification in treating any form of malnutrition was not evaluated.
As of March 30, 2022, two of five ongoing studies had been published as fulltext papers. 53,54 One of them proved to be ineligible to be included in this systematic review because it compared two different fortified food products. 53 The other study provides additional data for the outcomes haemoglobin, ferritin, zinc, and retinol concentrations, and on growth measures, 54 which do not change the conclusions. WHO guidelines recommend that: "In populations where anaemia is a public health problem, pointof use fortification of complementary foods with iron containing micronutrient powders in infants and young children aged 6-23 months is recommended, to improve iron status and reduce anaemia". 55 Our systematic review and metaanalysis shows that fortified foods formulated specifically for infants and young children might be an effective alternative.
This study has several strengths. First, we used a broad search strategy in both electronic databases and trial registries without applying date or language restrictions. It is unlikely that published trials have been missed; however, unpublished or ongoing trials not registered in clinical trial registries could be missing. Second, we aimed to reduce bias wherever possible by having at least two review authors work independently on trial selection, data extraction, and risk of bias and GRADE assessments.
A limitation of this systematic review is that several prespecified outcomes were investigated in a small number of trials or no data were available at all. Second, authors of ongoing studies were not contacted. We were able to explore the potential for publication bias using funnel plots only for the outcome haemoglobin con centration. Included studies were published between 1977 and 2020. Both the foods fortified and the micro nutrients used for fortification were diverse; most of the studies provided iron either alone or in combination with other micronutrients.
We checked other systematic reviews and meta analyses and investigated their agreements and dis agreements with our findings. We found two studies: one review assessed the effects of a wide range of iron containing interventions on anaemia and iron status in infants and children younger than 3 years, 56 and the other assessed the health effect of centrally processed micronutrientfortified dairy products and fortified cereal in children aged 6 months to 5 years. 57 These two reviews found that iron fortification increased haemoglobin concentrations and reduced anaemia. Developmental effects of a range of interventions, including micronutrientfortified complementary foods, were assessed in a systematic review in infants and children aged between 6 months and 2 years, 58 with only two included studies assessing the effects of fortified processed foods, both finding no effect on growth.
The findings of our review are generalisable to apparently healthy children in middleincome settings in Asia and Africa, although some children might have been at risk of having highly prevalent diseases such as malaria, diarrhoea, or malnutrition. In malariaendemic regions, malaria might be an additional cause of anaemia besides iron deficiency, infections, or other nutrient deficiencies, as the malaria parasite destroys erythrocytes. 9 In such regions, nutritional status results have to be interpreted cautiously because malaria substantially reduces haemo globin concen trations 59 and affects many other nutritional status indicators, including serum ferritin, serum transferrin, and plasma retinol. 60 Therefore, biomarkers of iron and vitamin A status should be statistically adjusted for malaria and the severity of infection. 61 Most of the included studies in our systematic review were done in malariaendemic areas; however, none reported adjustments for malaria. Thus, the effect of malaria on our results cannot be accurately judged.
Some studies suggest that fetal iron deficiency might be detrimental to early neurodevelopment, but early iron supplementation in anaemic infants can have a positive effect on developmental scores (both cognitive and motor), regardless of a country's income status. 62 Micronutrients as a sole intervention (ie, without an additional increase in macronutrient intake), however, seem to have no effect on growth.
Micronutrient deficiencies and their health con sequences remain a global health problem, and several factors, including age of the target population, baseline anaemia status, malaria prevalence, and presence of other causes of infection or inflammation, need to be considered. 22,63 Beside products from multinational companies, locally manufactured, lowercost fortified complementary food products are available in low income countries; however, access to these products is still far from optimal in several settings. 64,65 WHO states: "To ensure their success and sustainability, especially in resourcepoor countries, food fortification programmes should be implemented in concert with poverty reduction programmes and other agricultural, health, education and social intervention programmes that promote the consumption and uti l ization of adequate quantities of good quality nutritious foods among the nutritionally vulnerable." 9 Several research gaps have to be further explored. As provision of iron in any product that is given to infants and young children raises questions of safety, potential adverse effects have to be further explored in both malariaendemic and nonmalariaendemic settings. Studies should investigate whether consumption of fortified complementary foods has an effect on allcause mortality. It would be important to know what level of fortification can lead to adequate or excess nutrient intakes, affect stunting or wasting, or influence vitamin and mineral status other than iron. Further studies are required to answer the question under what circum stances the provision of fortified complementary foods to infants and young children is able to affect mental and motor skill development. Microbiota composition has not yet been investigated at all. How the consumption of such foods affects the intake of other foods, diet diversity, or breastfeeding time-ie, whether and to what extent they displace other foods-should also be determined.
Studies with both higher and lower nutrient content have to be done to determine dose-response effects.
Effects of complementary food fortification should be further investigated in lowincome and middle income countries, but should also be assessed in high income countries, and in regions where malaria is not endemic. Planned randomised controlled trials should be done with rigorous methodology and large sample sizes. Furthermore, there is a need to investigate the sustainability of different evidencebased inter ventions and factors that enhance or impede their implementation. 63 In conclusion, micronutrient deficiencies and their health consequences are a global problem, and fortified complementary food products might be one effective strategy to improve the micronutrient status of young children. There is a need to enhance these targeted, evidencebased interventions to prevent micronutrient deficiencies in infants and young children aged 6-23 months.

Contributors
MIM and SL were responsible for the development of the search strategy. MIM did the systematic searches. IC, RF, ÉS, and SL screened titles, abstracts, and full text. IC and RF extracted data. ÉS and SL assessed risk of bias. TF and SL did the statistical analyses. LS and SL did the GRADE assessment. IC, RF, ÉS, and SL prepared the first draft of the manuscript. All authors approved the final manuscript. SL was responsible for the coordination of tasks. IC and RF accessed and verified all data. The corresponding author had the final responsibility for the decision to submit for publication.

Declaration of interests
We declare no competing interests.

Data sharing
Full datasets can be obtained from the corresponding author.